Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.

Margaret Clapson,J.n. Flynn ,Jacob Hurst,Kuan-Hsiang Gary Huang,Leana Laker,Emily Adland,Philip Goulder ,Bruce D. Walker,Luisa Mori,Vas Novelli,Mary Carrington,Julia G. Prado,Thumbi Ndung’u,Roger Shapiro,Pieter Jooste,Vanessa Naidoo,Maximilian Muenchhoff,John Frater,Christina Thobakgale,Anna Csala,Andrew J. Prendergast ,Paolo Paioni

doi:10.1371/journal.ppat.1004954

Abstract

HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

Highlights

HIV-infected children typically progress more rapidly to AIDS than adults [1]
A principal mechanism by which this HLA effect is mediated is via viral replicative capacity (VRC), protective HLA alleles such as HLA-BÃ57 driving the selection of viral escape mutants that reduce VRC
We here address the role of HLA and VRC in pediatric disease progression in a large cohort in Kimberley, South Africa

Summary

Introduction

HIV-infected children typically progress more rapidly to AIDS than adults [1]. Without treatment, approximately 50% of HIV-1 infected children develop AIDS within a year and 50% will die before their second birthday in sub-Saharan Africa [1]. A minority of perinatally infected children remains asymptomatic through childhood despite being antiretroviral therapy (ART) naive. The reasons for this variation in pediatric disease progression remain largely unknown. Pediatric HIV infections have accounted for only approximately 10% of those arising in the global epidemic (http://www.avert.org/global-hiv-aids-epidemic.htm), they provide the potential to understand new mechanisms by which HIV disease can be avoided following infection. This remains an important goal of HIV research, with direct relevance to vaccine design

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